Derivatives of gylcero-manno-heptose adp for use in modulating immune response

Abstract

The disclosure provides compounds, compositions and methods related to activating alpha-kinase 1 (ALPK1) for modulating an immune response and treating or preventing cancer, infection, inflammation and related diseases and disorders as well as potentiating an immune response to a target antigen. The disclosure also provides heterocyclic compounds of formula (I) as agonists of alpha protein kinase 1 (ALPK1) and their use in activating ALPK1, modulating an immune response and treating diseases such as cancer, wherein A1, A2, L1, L2, L3, Z1, Z2, W1, W2, R1, R2, R3, R4, R5, R6 and R7 are as defined herein.

1 . A compound represented by formula (I): 
       
         
           
           
               
               
           
         
       
       and/or a stereoisomer, tautomer, stable isotope, prodrug or pharmaceutically acceptable salt thereof, wherein:
 A 1  and A 2  are independently selected from O, S and —C(R 8 R 9 )—, wherein
 R 8  and R 9  are independently selected from H, D, —OH, N 3 , —CN, halogen and an optional substituted group selected C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkanoyloxy, C1-C4 alkenyloxy and aralkyloxy, wherein the optional substituents are 1-3 substituents independently selected from D, halogen, —OH, ═O, C1-C4 alkyl and C1-C4 alkoxy; at least one of A 1  or A 2  is —C(R 8 R 9 ); 
 wherein R 8  or R 9  in A 1  can cyclize with R 8  or R 9  in A 2  to form C3-C6 cycloalkyl and heterocyclyl containing 3 to 9 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, each optionally substituted by 1-3 substituents independently selected from D, halogen, —OH, ═O, C1-C4 alkyl and C1-C4 alkoxy; 
 
 L 1  and L 2  are independently selected from O, CH 2 , CHF and CF 2 ; 
 L 3  is O, S or CH 2 ; 
 Z 1  and Z 2  are independently selected from O and S; 
 W 1  is —C(R 10 R 11 )—, wherein
 R 10  and R 11  are independently selected from H, D, —OH, halogen, and optionally substituted groups selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4-haloalkoxy, C1-C4 alkenyloxy, aralkyloxy, 1-6 membered oligopeptidyl linked via C-terminal C(O)O— and R 12 CO 2 —, wherein
 R 12  is selected from C1-C20 alkyl, C1-C20 alkenyl, C1-C20 alkoxy, C1-C20 alkenyloxy, C1-C20 alkylamino, C3-C6 cycloalkyl, heterocyclyl containing 4 to 6 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, C6-C10 aryl, and heteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members and 1-6 membered oligopeptidyl linked via N-terminal N; 
 
 wherein the optional substituents for R 10  and R 11  are 1-3 substituents independently selected from D, halogen, —OH, ═O, C1-C4 alkyl and C1-C4 alkoxy; 
 wherein when W 1  is —C(R 10 R 11 )— and R 10  is F, and the others are defined as above, W 2  is H or C1-C3 alkyl optionally substituted with 1-3 substituents independently selected from D, halogen, —OH, ═O, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 haloalkoxyl, C1-C3 alkenyloxyl and R 12 CO 2 —, wherein R 12  is C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C3-C6 cycloalkyl, cycloheteroalkyl containing 3 to 6 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, C6-C10 aryl, and heteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members; 
 
 W 2  is R 13 -Q 1 -W 3 —, wherein
 Q 1  is selected from —O— or —NH—, 
 W 3  is selected from a bond or C1-C3 alkylene groups optionally substituted with 1-3 substituents independently selected from halogen, —OH, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 alkenyloxy, 
 R 13  is 1-6 membered oligopeptidyl linked via C-terminal carbonyl group or 
 R 14 Q 2 C(O)—, wherein
 Q 2  is a bond, —O— or —NH—, 
 R 14  is 1-6 membered oligopeptidyl linked via N-terminal N or an optionally substituted group selected from C5-C20 alkyl, C5-C20 alkylenyl and R 15 -Q 3 -Q 4 -Q 5 -, wherein
 Q 3 ,Q 4  and Q 5  are independently selected from a bond, aryl, heteroaryl containing 5 to 6 ring atoms, C3-C6 cycloalkyl and heterocyclyl containing 4 to 6 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, and at least one of Q 3 , Q 4  and Q 5  is not a bond, 
 R 15  is an optionally substituted group selected from C1-C18 alky and C1-C18 alkoxy; 
 
 
 wherein the optional substituents for R 14  and R 15  are 1-3 substituents independently selected from halogen, —OH, —CO 2 H, C1-C4 alkyloxycarbony, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy C3-C6 cycloalkyl and C3-C6 cycloalkyloxy; 
 
 R 1  is aryl or heteroaryl containing 5 to 10 ring atoms and having 1-4 heteroatoms selected from N, O and S as ring members, wherein R 1  is optionally substituted with 1-3 substituents selected from D, halogen, —OH, ═O, CN, NH 2  and an optionally substituted group selected from C1-C4 alkyl, C1-C4 alkoxy, (R 16 R 17 )N— and (R 16 R 17 )NCO—, wherein
 R 16  and R 17  are independently selected from H and an optionally substituted group selected from C1-C4 alkyl, C3-C6 cycloalkyl, heterocyclyl containing 4 to 6 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, aryl, arylalkyl, heteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members; and heteroarylalkyl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members; wherein the optional substituents are 1-3 substituents independently selected from from D, halogen, —OH, ═O, CN, NH 2  and an C1-C4 alkyl, C1-C4 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy and C3-C6 cycloalkyl; 
 
 R 2 , R 3  and R 4  are independently selected from H, D, halogen, C1-C4 alkyl and C1-C4 haloalkyl; 
 R 5 , R 6  and R 7  are independently selected from H, —OH, halogen, and R 12 CO 2 —, and at least two of R 5 , R 6  and R 7  are OH or R 12 CO 2 —, wherein R 12  is selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkenyloxy, C1-C4 alkylamino, C3-C6 cycloalkyl, heterocyclyl containing 4 to 6 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, C6-C10 aryl, and heteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members;
 wherein any two of the adjacent groups of R 5 , R 6  and R 7  can cyclize to form heterocyclyl containing 5 to 9 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, each optionally substituted by 1-3 substituents independently selected from D, halogen, —OH, ═O, C1-C4 alkyl and C1-C4 alkoxy. 
 
 
     
     
         2 . The compound according to  claim 1 , which is a compound of Formula IA, and/or a stereoisomer, a stable isotope, prodrug or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
       wherein:
 Y 1  and Y 2  are independently selected from H, D, —OH, N 3 , —CN, halogen and optionally substituted groups selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkanoyloxy, C1-C4 alkenyloxy and aralkyloxy;
 wherein the optional substituents are 1-3 substituents independently selected from D, halogen, —OH, —O, C1-C4 alkyl and C1-C4 alkoxy; and 
 
 R 1 -R 7 , L 1 -L 3 , Z 1 , Z 2 , W 1  and W 2  are defined as in  claim 1 . 
 
     
     
         3 . The compound according to  claim 2 , wherein
 Y 1  and Y 2  are independently selected from H, D, —OH, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkanoyloxy and C1-C4 alkenyloxy;   R 1 -R 7 , L 1 -L 3 , Z 1 , Z 2 , W 1  and W 2  are defined as in  claim 1 .   
     
     
         4 . The compound according to  claim 2 , wherein
 Y 1  and Y 2  are independently selected from —OH, halogen, C1-C4 alkyl and C1-C4 alkanoyloxy;   R 1 -R 7 , L 1 -L 3 , Z 1 , Z 2 , W 1  and W 2  are defined as in  claim 1 .   
     
     
         5 . The compound according to  claim 1 , which is a compound of Formula IB, and/or a stereoisomer, a stable isotope, prodrug or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 n 1  and n 2  are each an integer independently selected from the group consisting of 0-2; 
 X 1  and X 2  are independently selected from H, D, —OH, N 3 , —CN, halogen and optionally substituted groups selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkanoyloxy, C1-C4 alkenyloxy and aralkyloxy;
 wherein the optional substituents are 1-3 substituents independently selected from D, halogen, —OH, ═O, C1-C4 alkyl and C1-C4 alkoxy; 
 
 R 1 -R 7 , L 1 -L 3 , Z 1 , Z 2 , W 1  and W 2  are defined as in  claim 1 . 
 
     
     
         6 . The compound according to  claim 5 , wherein n 1  and n 2  are each 0. 
     
     
         7 . The compound according to  claim 5 , wherein
 X 1  and X 2  are independently selected from H, D, and C1-C4 alkyl;   R 1 -R 7 , L 1 -L 3 , Z 1 , Z 2 , W 1  and W 2  are defined as in  claim 1 .   
     
     
         8 . The compound according to  claim 1 , which is a compound of Formula IC, and/or a stereoisomer, a stable isotope, prodrug or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 A 1  is —C(R 10 R 11 )—, O or S; 
 R 1 -R 11 , L 1 -L 3 , Z 1 , Z 2 , W 1  and W 2  are defined as in Formula I. 
 
     
     
         9 . The compound according to  claim 1 , wherein R 2 , R 3 , and R 4  are each H. 
     
     
         10 . The compound according to  claim 1 , wherein R 5 , R 6 , and R 7  are each independently selected from the group consisting of —OH, and C1-C4 alkanoyloxy. 
     
     
         11 . The compound according to  claim 1 , wherein L 3  is O. 
     
     
         12 . The compound according to  claim 1 , wherein L 2  is O. 
     
     
         13 . The compound according to  claim 1 , wherein L 1  is O or S. 
     
     
         14 . The compound according to  claim 1 , wherein W 1  is —C(R 10 R 11 )—, wherein R 10  and R 11  are independently selected from H, D, —OH, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4-haloalkoxy, C1-C4 alkanoyloxy, C1-C4 alkenyloxy and R 12 CO 2 —, wherein R 12  is selected from C1-C20 alkyl, C1-C20 alkoxy, C1-C20 alkanoyloxy and C1-C20 alkenyloxy. 
     
     
         15 . The compound according to  claim 1 , wherein W 1  is —C(R 10 R 11 )—, wherein R 10  and R 11  are independently selected from H, D, —OH, halogen and C1-C20 alkanoyloxy. 
     
     
         16 . The compound according to  claim 1 , wherein W 2  in formulas I, IA, IB, and IC is R 13 -Q 1 -W 3 —, wherein Q 1  is —O—; W 3  is a C1 alkylene group and R 13  wherein R 13  is 1-6 membered oligopeptidyl linked via C-terminal carbonyl group; 
     
     
         17 . The compound according to  claim 1 , wherein W 2  in formulas I, IA, IB, and IC is R 13 -Q 1 -W 3 —, wherein Q 1  is —O—; W 3  a C1 alkylene group and R 13  is R 14 Q 2 C(O)—; wherein R 14  is 1-6 membered oligopeptidyl linked via N-terminal group, Q 2  is a bond; 
     
     
         18 . The compound according to  claim 1 , wherein W 2  in formulas I, IA, IB, and IC is R 13 -Q 1 -W 3 —, wherein Q 1  is —O—; W 3  is a C1 alkylene group and R 13  is R 14 Q 2 C(O)—; wherein R 14  is an optionally substituted group selected from C5-C20 alkyl and C5-C20 alkylenyl; 
     
     
         19 . The compound according to  claim 1 , wherein W 2  in formulas I, IA, IB, and IC is R 13 -Q 1 -W 3 —, wherein
 Q 1  is —O—, 
 W 3  is a C1 alkylene group, and 
 R 13  is R 14 Q 2 C(O)—, wherein R 14  is an optionally substituted group selected from R 15 -Q 3 -Q 4 -Q 5 -; Q 3 ,Q 4  and Q 5  are independently selected from a bond, aryl, heteroaryl containing 5 to 6 ring atoms, C3-C6 cycloalkyl and heterocyclyl containing 4 to 6 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, and at least one of Q 3 , Q 4  and Q 5  is not a bond; and R 15  is an optionally substituted group selected from C1-C18 alky and C1-C18 alkoxy; 
 wherein the optional substituents for R 14  and R 15  are 1-3 substituents independently selected from halogen, —OH, —CO 2 H, C1-C4 alkyloxycarbony, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy C3-C6 cycloalkyl and C3-C6 cycloalkyloxy. 
 
     
     
         20 . The compound according to  claim 1 , wherein W 2  in formulas I, IA, IB, and IC is R 13 -Q L -W 3 —, wherein
 Q L  is —O—, 
 W 3  is a C1 alkylene group and 
 R 13  is R 14 Q 2 C(O)—, wherein
 R 14  is an optionally substituted group selected from R 15 -Q 3 -Q 4 -Q 5 -; Q 3 ,Q 4  and Q 5  are independently selected from a bond, aryl, and at least one of Q 3 , Q 4  and Q 5  is not a bond; R 15  is an optionally substituted group selected from C1-C18 alky and C1-C18 alkoxy, 
 wherein the optional substituents for R 14  and R 15  are 1-3 substituents independently selected from halogen, —OH, —CO 2 H, C1-C4 alkyloxycarbony, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy C3-C6 cycloalkyl and C3-C6 cycloalkyloxy. 
 
 
     
     
         21 . The compound according to  claim 1 , wherein W 2  in formulas I, IA, IB, and IC is R 13 -Q L -W 3 —, wherein Q 1  is —O—; W 3  is a C1 alkylene group and R 13  is R 14 Q 2 C(O)—; wherein R 14  is is an optionally substituted group selected from C5-C20 alkyl group and Q 2  is a bond. 
     
     
         22 . The compound according to  claim 1 , wherein R 1  is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         23 . The compound according to  claim 1 , wherein R 1  is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         24 . The compound according to  claim 1 , wherein R 1  is selected from 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound according to  claim 1 , wherein R 1  is selected from 
       
         
           
           
               
               
           
         
         R 18  and R 19  are independently selected from H and an optionally substituted group selected from heterocyclyl C6-C10 arylalkyl, heteroarylalkyl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members, R 20 CO— and R 21 S(O) 2 —; wherein the substitutents for 1-3 substituents independently selected from halogen, OH, ═O, CN, NH 2 , C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyloxy, C1-C3 haloalkyloxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, heterocyclyl containing 4 to 6 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, C6-C10 aryl, C6-C10 haloaryl, heteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members, and haloheteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members; R 20  and R 21  are C1-C20 alkyl, C1-C20 alkenyl, heterocyclyl containing 4 to 6 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, C6-C10 aryl, C6-C10 haloaryl, heteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members, and haloheteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members. 
       
     
     
         26 . The compound according to  claim 1 , wherein R 1  is selected from 
       
         
           
           
               
               
           
         
         wherein R 22  and R 23  are independently selected from H, D halogen, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 haloalkyl, C1-C4 haloalkyloxy, C1-C4-cycloalkyl and C1-C4-cycloalkyloxy. 
       
     
     
         27 . The compound according to  claim 1 , which is a compound of Formula ID, and/or a stereoisomer, a stable isotope, prodrug or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 5 -R 7 , R 10 , R 14 , R 18 , Q 1 , Y1, Y 2 , Z 1  and Z 2  are as defined above. 
       
     
     
         28 . The compound according to  claim 1 , which is a compound of Formula IE, and/or a stereoisomer, a stable isotope, prodrug or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 Z 1  and Z 2  are independently selected from O and S wherein at least one of Z 1  and Z 2  is S; 
 W 2  is H or C1-C3 alkyl optionally substituted with 1-3 substituents independently selected from D, halogen, —OH, ═O, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 haloalkoxyl, C1-C3 alkenyloxyl and R 12 CO 2 —, wherein R 12  is C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C5-C20 alkyl, C5-C20 alkenyl, C5-C20 alkoxy, C5-C20 alkenyloxy, C5-C20 alkylamino, C3-C6 cycloalkyl, cycloheteroalkyl containing 3 to 6 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, C6-C10 aryl, and heteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members;
 R 1 -R 7 , R 11 , L 1 -L 3 , Y 1 Y2, and W 2  are defined above. 
 
 
     
     
         29 . The compound according to  claim 28 , Z 2  is S and Z 1  is O. 
     
     
         30 . The compound according to  claim 28 , Z 2  is S and Z 1  is S. 
     
     
         31 . The compound according to  claim 28 , R 2 , R 3 , and R 4  are each H. 
     
     
         32 . The compound according to  claim 28 , R 5 , R 6 , and R 7  are each independently selected from the group consisting of —OH, and C1-C4 alkanoyloxyl. 
     
     
         33 . The compound according to  claim 28 , L 3  is O. 
     
     
         34 . The compound according to  claim 28 , L 2  is O. 
     
     
         35 . The compound according to  claim 28 , L 1  is O. 
     
     
         36 . The compound according to  claim 28 , R 11  is selected from H, D, —OH, halogen, C1-C4 alkyl, C1-C4 alkoxyl, C1-C4 haloalkyl, C1-C4-haloalkoxyl, C1-C4 alkanoyloxyl, C1-C4 alkenyloxyl and R 12 CO 2 —, wherein R 12  is selected from C1-C4 alkyl, C1-C4 alkoxyl, C1-C4 alkanoyloxyl and C1-C4 alkenyloxyl. 
     
     
         37 . The compound according to  claim 28 , R 11  is selected from H, D, —OH, and halogen. 
     
     
         38 . The compound according to  claim 28 , R 11  is H. 
     
     
         39 . The compound according to  claim 28 , W 2  is C1-C3 alkyl optionally substituted with 1-3 substituents independently selected from D, halogen, —OH, ═O and C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 haloalkoxyl, C1-C3 alkenyloxyl and R 12 CO 2 —, wherein R 12  is C1-C alkyl, C1-C4 alkoxy and C1-C4 alkylamino. 
     
     
         40 . The compound according to  claim 28 , W 2  is C1-C3 alkyl optionally substituted with 1-3 substituents independently selected from D, halogen, —OH and R 12 CO 2 —, wherein R 12  is C1-C3 alkyl. 
     
     
         41 . The compound according to  claim 28 , W 2  is C1 alkyl optionally substituted with 1 substituent selected from —OH and R 12 CO 2 —, wherein R 12  is C1-C3 alkyl. 
     
     
         42 . The compound according to  claim 28 , R 1  in formulas IE is selected from 
       
         
           
           
               
               
           
         
       
     
     
         43 . The compound according to  claim 28 , when W 2  is R 1 CO 2 —, wherein R 12  is selected from C5-C20 alkyl, C5-C20 alkenyl, C5-C20 alkoxy, C5-C20 alkenyloxy, C5-C20 alkylamino, and R 1  in formulas IE is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         44 . The compound according to  claim 28 , R 1  in formulas IE is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         45 . The compound according to  claim 28 , R 1  in formulas IE is selected from 
       
         
           
           
               
               
           
         
       
     
     
         46 . The compound according to  claim 28 , R 1  in formulas IE is selected from 
       
         
           
           
               
               
           
         
         R 18  and R 19  are independently selected from H and an optionally substituted group (“OSG”) selected from heterocyclyl C6-C10 arylalkyl, heteroarylalkyl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members, R 20 CO— and R 21 S(O) 2 —; 
         wherein the substituents for the optionally substituted group (“OSG”) are 1-3 substituents independently selected from halogen, OH, ═O, CN, NH 2 , C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyloxy, C1-C3 haloalkyloxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, heterocyclyl containing 4 to 6 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, C6-C10 aryl, C6-C10 haloaryl, heteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members, and haloheteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members; and 
         R 20  and R 21  are C1-C20 alkyl, C1-C20 alkenyl, heterocyclyl containing 4 to 6 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, C6-C10 aryl, C6-C10 haloaryl, heteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members, and haloheteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members. 
       
     
     
         47 . The compound according to any one of  claim 28 , wherein R 1  in formulas IE is selected from 
       
         
           
           
               
               
           
         
         wherein R 22  and R 23  are independently selected from H, D halogen, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 haloalkyl, C1-C4 haloalkyloxy, C1-C4-cycloalkyl and C1-C4-cycloalkyloxy. 
       
     
     
         48 . The compound according to any one of  claim 28 , when W 2  is R 12 CO 2 —, wherein R 12  is selected from C5-C20 alkyl, C5-C20 alkenyl, C5-C20 alkoxy, C5-C20 alkenyloxy, C5-C20 alkylamino, wherein R 1  in formulas IE is 
       
         
           
           
               
               
           
         
       
     
     
         49 . The compound according to  claim 28 , wherein Y 1  and Y 2  are independently selected from H, D, —OH, halogen, C1-C4 alkyl, C1-C4 alkoxyl, C1-C4 haloalkyl, C1-C4 haloalkoxyl, C1-C4 alkanoyloxyl and C1-C4 alkenyloxyl. 
     
     
         50 . The compound according to  claim 28 , wherein Y 1  and Y 2  are independently selected from —OH, halogen, C1-C4 alkyl and C1-C4 alkanoyloxyl. 
     
     
         51 . The compound according to  claim 28 , wherein Y 1  and Y 2  are each —OH. 
     
     
         52 . The compound according to  claim 28 , wherein the compound of formula IE is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         53 . The compound according to  claim 1 , wherein the compound of Formula I is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and/or a stereoisomer, a stable isotope, prodrug or a pharmaceutically acceptable salt thereof. 
     
     
         54 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         55 . A method for activating ALPK1, the method comprising administering an effective amount of a compound or a pharmaceutically acceptable salt of  claim 1 . 
     
     
         56 . A method for modulating an immune response in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt of  claim 1 . 
     
     
         57 . A method for treating cancer in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt of  claim 1 . 
     
     
         58 . A method for potentiating an immune response to a target antigen in a subject, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt of  claim 1 . 
     
     
         59 . A method for treating a disease or disorder amendable to treatment by activation of NFkB, p38, and JNK cell signaling pathways in cells of a subject, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt of  claim 1 . 
     
     
         60 . A method for treating or preventing a disease or disorder caused by an infectious agent selected from a bacteria, virus, or parasite in a subject in need thereof, the comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt of  claim 1 . 
     
     
         61 . The method of  claim 56 , wherein modulating an immune response is selected from activation of innate immunity and activation of adaptive immunity. 
     
     
         62 . The method of  claim 57 , wherein the cancer is selected from soft tissue sarcoma, breast cancer, head and neck cancer, melanoma, cervical cancer, bladder cancer, hematologic malignancy, glioblastoma, pancreatic cancer, prostate cancer, colon cancer, breast cancer, renal cancer, lung cancer, merkel cell carcinoma, small intestine cancer, thyroid cancer, acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), gastric cancer, gastrointestinal stromal tumors, non-Hodgkins lymphoma, Hodgkins lymphoma, liver cancer, leukemia, lymphoma, T-cell lymphoma, brain cancer, and multiple myeloma. 
     
     
         63 . The method of  claim 58 , wherein the target antigen is an antigen of an infectious agent selected from the group consisting of adenovirus, Coxsackie B virus, cytomegalovirus, eastern equine encephalitis virus, ebola virus, enterovirus 71, Epstein-Barr virus,  Haemophilus influenzae  type b (Hib), hepatitis C virus (HCV), herpes virus, human immunodeficiency virus (HIV), human papillomavirus (HPV), hookworm, Marburg virus, norovirus, respiratory syncytial virus (RSV), rotavirus,  Salmonella typhi, Staphylococcus aureus, Streptococcus pyogenes , varicella, West Nile virus,  Yersinia pestis , and Zika virus. 
     
     
         64 . The method of  claim 58 , wherein the compound acts as a vaccine adjuvant for a vaccine in the treatment or prevention of anthrax, caries, Chagas disease, dengue, diphtheria, ehrlichiosis, hepatitis A or B, herpes, seasonal influenza, Japanese encephalitis, leprosy, lyme disease, malaria, measles, mumps, meningococcal disease, including meningitis and septicemia, Onchocerciasis river blindness, pertussis (whooping cough), pneumococcal disease, polio, rabies, rubella, schistosomiasis, severe acute respiratory syndrome (SARS), shingles, smallpox, syphilis, tetanus, tuberculosis, tularemia, tick-borne encephalitis virus, typhoid fever, trypanosomiasis, yellow fever, or visceral leishmaniasis. 
     
     
         65 . The method of  claim 59 , wherein the disease or disorder is selected from tuberculosis, meningitis, pneumonia, ulcer, sepsis, rhinitis, asthma, allergy, COPD, inflammatory bowel disease, arthritis, obesity, radiation-induced inflammation, psoriasis, atopic dermatitis, non-alcoholic steatohepatitis (NASH), Alzheimer's disease, systemic lupus, erythematosus (SLE), autoimmune thyroiditis (Grave's disease), multiple sclerosis, ankylosing spondylitis bullous diseases, actinic keratoses, ulcerative colitis, Crohn's disease, alopecia areata, and diseases and disorders caused by the hepatitis C virus (HCV), the hepatitis B virus (HBV), or the human immunodeficiency virus (HIV). 
     
     
         66 . The method of  claim 60 , wherein the infectious agent is a bacteria. 
     
     
         67 . The method of  claim 60 , wherein the infectious agent is a virus. 
     
     
         68 . The method of  claim 60 , wherein the infectious agent is a parasite. 
     
     
         69 . The method of  claim 66 , wherein the bacteria is a Gram-negative or a Gram-positive bacteria. 
     
     
         70 . The method of  claim 69 , wherein the Gram-negative bacteria is selected from the group consisting of  Acinetobacter baumanii, Aggregatobacter actinomycetemcomitans, Bartonella bacilliformis, Bartonella, henselae, Bartonella quintana, Bifidobacterium Borrelia, Bortadella pertussis, Brucella  sp,  Burkholderia cepacis, Burkholderia psedomallei, Campylobacter jejuni, Cardiobacterium hominis, Campylobacter fetus, Chlamydia pneumonia, Chlymydia trahomatis, Clostridium difficile, Cyanobacteria, Eikennella corrodens, Enterobacter, Enterococcus faccium, Escherichia coli, Escherichia coli  0157 , Franceilla tularensis, Fusobacterium nucleatum, Haemophilus influenza, Haemophilus aphrophilus, Haemophilus ducreyi, Haemophilus parainfluenzae, Helicobacter pylori, Kingella kingae, Klebsiella pneumonia, Legionella bacteria, Legionella pneumophila serogroup  1, Leptospria,  Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Proteus myxofaciens, Providencia rettgeri, Providencia alcalifaciens, Providencia stuartii, Pseudomonas aeruginosa, Pseudomonas paucimobilis, Pseudomonas putida Pseudomonas fluorescens, Pseudomonas acidovorans , Rickettsiae,  Salmonella enterica, Salmonella typhi, Salmonella paratyphi types A, B typhus, Salmonella, dublin, Salmonella arizonae, Salmonella choleraesuis, Serratia marcescens, Schigella dysenteriae, Schigella flexneri, Schigella boydii, Schigella sonnei, Treponema, Stenotrophomonas maltophilia, Vibrio cholerae, Vibrio mimicus, Vibrio alginolyticus, Vibrio hollisae, Vibrio parahaemolyticus, Vibrio vulnificus  and  Yersinia  pestitis. 
     
     
         71 . The method of  claim 69 , wherein the Gram-positive bacteria selected from the group consisting of Actinomycetes,  Bacillus anthracis, Bacillus subtilis, Clostridium tetani, Clostridium, perfingens, Clostridium botulinum, Clostridium tetani, Corynebacterium diphtheriae, Enterococcus faecalis, Enterococcus faecium, Erysipelothrix ruhsiopathiae, Listeria monocytogenes, Mycobacterium leprae, Mycobacterium tuberculosis, Mycoplasma, Nocardia, Propionibacerium, Pseudomonas aeruginosa, Pneumococci, Staphylococcus aureus, Staphylococcus epidermidis , methicillin resistant  Staphylococcus aureus  (MRSA), vancomycin resistant  Staphylococcus aureus  (VRSA),  Staphylococcus lugdunensis, Staphylococcus saprophyticus, Streptococcus pneumonia, Streptococcus pyogenes , and  Streptococcus mutants.    
     
     
         72 . The method of  claim 67 , wherein the virus is selected from the group consisting of ebolavirus, hepatitis B virus, hepatitis C virus, herpes simplex virus, human immunodeficiency virus (HIV), human papillomavirus (HPV-6, HPV-11), human SARS coronavirus, influenza A virus, influenza B virus, influenza C virus, measles virus, rabies virus, poliovirus, SARS corona virus, and yellow fever virus. 
     
     
         73 . The method of  claim 68 , wherein the parasite is selected from the group consisting of  Acanthamoeba  spp,  American trypanosomiasis, Balamuthia mandnillanis, Babesia divergenes, Babesia bigemina, Babesia equi, Babesia microfti, Babesia duncani, Balantidium coli, Blastocystis  spp  Cryptosporidium  spp,  Cyclospora cayetanensis, dientamoeba fragilis, Diphyllobothrium latum, Leishmania amazonesis, Naegleria fowderi, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale curtisi, Plasmodium malariae, Rhinosporidium seeberi, Sarcocystis bovihominis, Sarcocystiss suihominis, Toxoplasma gondii, Trichmonas vaginalis, Trypanosoma brucei, Trypanosoma cruzi , and  Taenia multiceps.    
     
     
         74 . The method of  claim 56 , further comprising administering to the subject one or more additional therapeutic agents or immune modulators, and combinations thereof. 
     
     
         75 . The method of  claim 74 , wherein the one or more additional therapeutic agents is selected from an anti-microbial agent, such as an anti-bacterial agent, an anti-viral agent, or an anti-parasitic agent, an anti-cancer agent, or a therapeutic agent for the treatment of tuberculosis, meningitis, pneumonia, ulcer, sepsis, rhinitis, asthma, allergy, COPD, inflammatory bowel disease, arthritis, obesity, radiation-induced inflammation, psoriasis, atopic dermatitis, non-alcoholic steatohepatitis (NASH), Alzheimer's disease, systemic lupus, erythematosus (SLE), autoimmune thyroiditis (Grave's disease), multiple sclerosis, and ankylosing spondylitis bullous diseases. 
     
     
         76 . The method of  claim 74 , wherein the one or more additional immune modulators is selected from the group consisting of an inhibitor or antagonist of an immune checkpoint regulator, a vaccine, preferably a vaccine against an immune checkpoint regulator, an immune stimulatory molecule, an agonist of an immune co-stimulatory molecule, a recombinant protein, and a T cell, preferably a chimeric antigen receptor T (CAR-T) cell. 
     
     
         77 . The method of  claim 76 , wherein the immune checkpoint regulator is selected from the programed cell death 1 (PD-1) receptor (CD279), a ligand of PD-1 (e.g., PD-L1), cytotoxic T-lymphocyte associated protein 4 (CTLA4), tumor necrosis factor receptor superfamily member 9 (alternatively TNFRSF9, 4-1BB) and 4-1BB ligands, tumor necrosis factor receptor superfamily member 4 (alternatively TNFRSF4, OX40) and OX40 ligands, glucocorticoid-induced TNFR-related protein (GITR), Tumor Necrosis Factor Receptor Superfamily Member 7 (alternatively TNFRSF7, cluster of differentiation 27, CD27), TNFRSF25 and TNF-like ligand 1A (TL1A), TNF Receptor Superfamily Member 5 (alternatively TNFRSF5, CD40) and CD40 ligand, Herpesvirus entry mediator (HVEM)-tumor necrosis factor ligand superfamily member 14 (alternatively TNFSF14, LIGHT)-lymphotoxin alpha (LTA), herpesvirus entry mediator-(HVEM)-B- and T-lymphocyte attenuator (BTLA)-CD160 (alternatively TNFSF14), lymphocyte activating gene 3 (LAG3), T-cell immunoglobulin and mucin-domain containing-3 (TIM3), sialic-acid-binding immunoglobulin-like lectins (SIGLECs), inducible T-cell costimulator (ICOS) and ICOS ligand, B7-H3 (B7 family, alternatively CD276), V-set domain-containing T-cell activation inhibitor 1 (VTCN1, alternatively B7-H4), V-Type immunoglobulin domain-containing suppressor of T-cell activation (VISTA), human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2)-transmembrane and Immunoglobulin domain containing 2 (TMIGD2), butyrophilins, natural killer cell receptor 2B4 (alternatively NKR2B4, CD244) and B-Cell Membrane Protein (CD48), T-Cell Immunoreceptor with Immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) and Poliovirus receptor (PVR) family members, killer-cell immunoglobulin-like receptors (KIRs), Immunoglobulin-like transcripts (ILTs) and leukocyte immunoglobulin-like receptor (LIRs), natural killer group protein 2 member D (NKG2D) and natural killer group protein 2 member A (NKG2A), major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) and MHC class I polypeptide-related sequence B (MICB), natural killer cell receptor 2B4 (CD244), colony stimulating factor 1 receptor (CSF1R), indoleamine 2,3-dioxygenase (IDO), transforming growth factor beta (TGFβ), Adenosine-ecto-nucleotidase triphosphate diphosphohydrolase 1 (CD39)-5′-nucleotidase (CD73), C-X-C motif chemokine receptor 4 (CXCR4) and C-X-C motif chemokine ligand 12 (CXCL12), phosphatidylserine, signal regulatory protein alpha (SIRPA) and integrin associated protein (CD47), vascular endothelial growth factor (VEGF), and neuropilin. 
     
     
         78 . The method of  claim 76 , wherein the one or more additional immune modulators is a vaccine. 
     
     
         79 . The method of  claim 76 , in a method for treating cancer, wherein the vaccine is a vaccine against a tumor antigen. 
     
     
         80 . The method of  claim 79 , wherein the tumor antigen is selected from glycoprotein 100 (gp100), mucin 1 (MUC1), and melanoma-associated antigen 3 (MAGEA3). 
     
     
         81 . The method of  claim 76 , wherein the one or more additional immune modulators is a T cell, preferably a chimeric antigen receptor T cell. 
     
     
         82 . The method of  claim 76 , wherein the one or more additional immune modulators is a recombinant protein, preferably selected from granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 7 (IL-7), IL-12, IL-15, IL-18, and IL-21. 
     
     
         83 . The method of  claim 56 , wherein the composition comprises a compound or a pharmaceutically acceptable salt of any one of  claims 1  to  51 . 
     
     
         84 . The method of  claim 76 , wherein the one or more additional immune modulators is an inhibitor or antagonist of an immune checkpoint regulator, preferably a PD-1/PD-L1 inhibitor. 
     
     
         85 . The method of  claim 84 , wherein the PD-1/PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, BMS-936559, atezolizumab, durvalumab, and avelumab. 
     
     
         86 . The method of any one of  claim 57 , wherein the cancer is selected from advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, Hodgkin's lymphoma, liver cancer, gastric cancer, colon cancer, breast cancer, non-Hodgkin's lymphoma, prostate cancer, head and neck cancer, thyroid cancer, brain cancer, acute myeloid leukemia (AML), merkel cell carcinoma, multiple myeloma, cervical cancer, and sarcoma. 
     
     
         87 . A method for treating cancer in a subject in need of such treatment, the method comprising administering to the subject a composition comprising a compound of  claim 1 , and an immune modulator selected from one or more of an inhibitor or antagonist of an immune checkpoint regulator, an immune stimulatory molecule, and an agonist of an immune co-stimulatory molecule. 
     
     
         88 . The method of  claim 87 , wherein the inhibitor or antagonist of an immune checkpoint regulator is a PD-1/PD-L1 inhibitor. 
     
     
         89 . The method of  claim 88 , wherein the PD-1/PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, BMS-936559, atezolizumab, durvalumab, and avelumab. 
     
     
         90 . The method of  claim 87 , wherein the immune modulator is selected from interferon alpha (INFα), a stimulator of interferon genes (“STING”) agonist, a TLR agonist (e.g., resquimod), and an anti-OX40 (CD134) agonist antibody. 
     
     
         91 . The method of  claim 87 , wherein the immune modulator is an agonist of an immune co-stimulatory molecule. 
     
     
         92 . The method of  claim 91 , wherein the agonist of an immune co-stimulatory molecule is an anti-OX40 (CD134) agonist antibody. 
     
     
         93 . A method for treating a liver disease or disorder in a subject in need of such treatment, the method comprising administering a compound or a pharmaceutically acceptable salt of  claim 1  to the subject. 
     
     
         94 . The method of  claim 93 , wherein the liver disease or disorder is selected from liver cancer, non-alcoholic steatohepatitis (NASH), and a disease or disorder caused by infection with the hepatitis C virus (HCV) or the hepatitis B virus (HBV). 
     
     
         95 . The method of  claim 56 , wherein the subject is a vertebrate. 
     
     
         96 . The method of  claim 56 , wherein the subject is a human. 
     
     
         97 . A vaccine composition or vaccine adjuvant composition comprising a compound or a pharmaceutically acceptable salt of  claim 1 . 
     
     
         98 . A pharmaceutical composition, a vaccine composition, or a vaccine adjuvant composition comprising a compound or a pharmaceutically acceptable salt of  claim 1 .